Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin secreting a-cells. Cytokines have been implicated as effector molecules that participate in both islet inflammation and a-cell destruction during the development of IDDM. In this study the effects of cytokines on the expression of inducible nitric oxide synthase (INOS) and inducible cyclooxygenase (COX-2) by human islets were examined. In combination, the cytokines, IL-IB, TNF-a, and IFN-y induce the time-dependent formation of nitrite and prostaglandin E2 (PGE2) by human islets. The nitric oxide synthase inhibitor NG-monomethyl-L- arginine (NMMA) completely inhibits cytokine-induced nitrite formation and attenuates PGE2 production by human islets. NMMA does not inhibit cytokine-induced expression of COX-2 by human islets suggesting that nitric oxide may directly activate cyclooxygenase, an effect that has been previously demonstrated for isolated rat islets. This combination of cytokines (IL1-1B, TNF-a and IFN-y) also induces the expression of iNOS mRNA by human islets as demonstrated both by reverse transcriptase polymerase chain reaction (RT-PCR), and Northern blot analysis. We further show that the tyrosine kinase inhibitors genistein and herbimycin A prevent IL-1B + IFN-y-induced expression of COX-2 and iNOS, and the production of PGE2 and nitric oxide by human islets. These results demonstrate that cytokines induce the expression of iNOS and COX-2 by human islets, and that cytokine-induced expression of both COX-2 and iNOS by human islets appear to require the activation of a tyrosine kinase(s).